Preparation of pharmaceutical unit dosage forms

ABSTRACT

Pharmaceutical dosage forms comprising an edible web having deposited thereon or at least partially thereon a particulate medicament, the webs being thereafter fabricated and finished to pharmaceutically elegant solid dosage forms having no medicament exposed on an exterior surface. The dosage forms have a consistency of release of medicament which can be controlled to exacting specifications. The disclosed solid dosage forms are prepared by high speed automated equipment and the process by which they are made is characterized by non-destructive quality control analysis and performance evaluation both conducted on-line and integrated into the manufacturing operation. Included in the scope of the disclosed invention are certain apparatus and methods of manufacture.

BACKGROUND OF THE INVENTION

The orally administered solid unit dosage forms heretofore recognized inthe pharmaceutical industry are generally divisible into two basicforms, i.e., tablets and capsules. There are various broad categories ofboth tablets and capsules recognized in the art such as, for example,those which are enteric coated to release medication in the intestinaltract, those which, by various mechanisms, release medication over anextended period of time, effervescents and the like. By and large suchconventional solid oral dosage forms suffer from a number ofdisadvantages.

First, conventional solid oral unit dosage forms are disadvantageous inthat each contains, admixed with the active ingredient, a plurality ofvarious substances which are termed "therapeutically inert or non-toxic,pharmaceutical adjunct materials". Such materials fall under theart-recognized categories of diluents, excipients, binders, lubricants,disintegrants, stabilizers, buffers, preservatives and the like.Although these materials are recognized as indispensible in the art ofpharmaceutical compounding, their use nonetheless presents problemswhich must be dealt with from a viewpoint of cost, final size and weightof the dosage unit and the like. Additionally, each such adjunctmaterial must be evaluated before use in terms of potentialincompatibilities with the medicaments present. Further, certain ofthese materials, e.g., lubricants, may present problems concerning thebioavailability of the active ingredient. Also, the presence of suchmaterials must be considered in analytical procedures utilized to testfor potency etc. of the finished dosage form.

A second primary disadvantage in solid oral unit dosage forms known tothe art is that the methods available for assay thereof involvedestruction of the dosage form thereby permitting the testing of only asmall percentage of such forms actually produced. Therefore, it isrecognized in the art that there can be considerable deviation within agiven batch of such dosage forms since the mean of dosage, performance,etc. for each batch deviation is determined by analysis of a relativelyminor number of samples.

The batch concept in itself is a disadvantage to prior art oral soliddosage forms simply from the viewpoint of the economics of the batchdesignation, control and evaluation.

In accordance with the present invention, solid dosage units primarilyfor oral ingestion are provided which are producible in large numbers athigh speed and, because they are prepared by a method unique in thepharmaceutical industry, they do not suffer from the above enumerateddisadvantages of currently available solid oral dosage forms, i.e.,tablets and capsules. This method is highly advantageous in that it:eliminates the necessity for batch requirements as they areconventionally recognized; provides for continuous on-line analysis forpotency as well as on-line performance evaluation of the dosage forms asthey are being produced; provides the substantial elimination of thenecessity of mixing conventional pharmaceutical adjunct materials withthe medicaments with the exception of glidants which may be required tofacilitate the flow of powders and/or certain other materialsadvantageous for product performance; and provides pharmaceuticallyelegant unit dosage forms which can be engineered to release medicamentat any desired rate and which are capable of a rate of release fasterthan commercial tablets and capsules presently available. In summary,the dosage forms of the invention provide assurance that a largerpercent of a more accurately measured amount of medication will beavailable in a more precisely controlled time after ingestion than isthe case with present commercial units.

The oral unit dosage forms of the present invention are advantageous ina number of important respects, foremost of which is the fact that theyare substantially qualified by on-line procedures during high-speed,substantially automated manufacturing operations. In addition, thedosage forms of the present invention are also advantageous in that themedicament contained therein is released for absorption with exceptionaluniformity over a large number of dosage units. Further, the dosageunits of the invention can be engineered to release medication within ashorter period of time after ingestion than is possible with solid oraldosage forms, e.g., tablets and capsules, presently available.Therefore, the dosage units of the invention provide superiorconsistency both in content of medicament and release thereof forabsorption.

Regarding the prior art, the following publications, which are directedto solid dosage forms distinguishable from conventional tablets arenoteworthy. Russell, U.S. Pat. No. 3,444,858 issued May 20, 1969describes a vehicle for the buccal administration of medicamentscomprising a strip of gelatinous material containing medication, saidstrip being divided into sections each of which is connected to the nextby easily tearable ligaments. In use, a section is merely separated fromthe strip and placed in the mouth.

A second publication warranting mention is an article in the New EnglandJournal of Medicine, Vol. 289, No. 10 pp. 533-5 (1973). This articledescribes a means whereby birth control medication is being madeavailable to women in the Peoples Republic of China on a very largescale. In this method, a sheet of colored, water-soluble,carboxymethylcellulose paper is treated with a solution ofprogestational and estrogenic materials. The sheet is then perforatedand cut into strips. The medicament is packaged as a strip of 22"squares" which are torn from the strip and taken daily. This methoddoes not provide for the concealment of the drug in the final dosageform, thereby suffering from the disadvantage of potential contaminationand/or inactivation of the medication once the package is opened.Further, by virtue of not being completely unitized, such perforatedstrips can give rise to uneven tearing at the perforations andpotentially, disproportionant dosage.

Finally to be considered is Higuchi et al. U.S. Pat. 3,625,214 issuedDec. 7, 1971 which describes a dosage form utilized for controlled,i.e., sustained release of medicaments. The dosage form is comprised, inessence, of a medicament containing martix which is coated on asubstrate which is then spiral wound to a final "jelly roll" appearance.After ingestion, the medicament is released by the gradual erosion ofthe outer layers of substrate and also by diffusion from the sides wherethere is exposed medicament. There is no disclosure of whether thedisclosed dosage forms are amenable to high capacity pharmaceuticalmanufacturing. There is further no disclosure of means whereby thedisclosed dosage forms can be rendered into pharmaceutically elegantfinished products.

In distinct contrast to the teachings of the foregoing publications, thenovel solid dosage units of the present invention are completelyunitized, amenable to non destructive, on-line analytical testing duringhigh capacity pharmaceutical manufacturing operations, are essentiallyfree from pharmaceutical adjunct materials that may interfere withperformance, have no exposed medicament and have a superior consistencyof release of medicament which enhances the efficacy thereof.

BRIEF STATEMENT OF THE INVENTION

Solid, unit dosage forms primarily for oral administration comprising anedible web of paper and/or polymeric materials having deposited thereonor at least partially thereon one or more medicaments having essentiallyno pharmaceutical adjunct materials admixed therewith, said web beingfabricated into an ingestible; pharmaceutically and cosmeticallyacceptable shape and sealed so as to have no exposed medicament aredisclosed. The unit dosage forms are prepared by high capacitypharmaceutical manufacturing techniques utilizing, in certain instances,novel apparatus. The manufacturing process includes means tonon-destructively test the dosage forms on-line to determine the amountof medicament which has been loaded to the web prior to the fabricationthereby assaying the potency of the finished dosage units by physicalparameters.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to solid, unit dosage forms primarilyfor oral ingestion which are advantageous in a number of particularsover present solid oral dosage forms, i.e., tablets and capsules. First,the fact that the dosage units of the invention are substantially freeof conventional pharmaceutical adjunct materials results in a savings incost of raw materials and manufacturing procedures as well aseliminating potential incompatibilities caused by the presence of suchmaterials. The distinction must be made here between the webs of theinvention which can be considered adjunct material and the materialssuch as fillers, binders and the like which are admixed with themedicament in conventional solid dosage forms.

Second, because the solid unit dosage forms of the invention areprepared continuously and subjected to on-line, non-destructiveanalytical procedures, the requirement for batch lot manufacturing as itis known today is eliminated thereby realizing a considerable economicsaving and a substantially improved level of quality control viewed interms of the finished dosage units. The fact that the manufacturingoperation of the invention includes means to feed back information froma testing station to the manufacturing procedures immediately preceedingit thus affording on-line corrections and adjustments. Such meansfacilitate the removal of only a small number of dosage units from anynumber designated as a manufacturing lot, i.e., from the positivereading immediately preceding a negative reading to the next followingpositive reading. The designation and removal of such small quantitiesof dosage forms thus avoids "poisoning of the barrel" and realizes botha large economic advantage over present pharmaceutical manufacturingprocedures and a superior level of qualtiy control particularly in termsof the active ingredient content in the finished dosage forms. In normaloperation, the dosage form of the invention are manufactured by time lotprocedures, i.e., a "lot" of dosage forms constitutes the numberprepared between two given points in time. This concept is believed tobe unique in the pharmaceutical industry. It will be appreciated,however, that some destructive testing will be required in anypharmaceutical manufacturing procedure as a check of performance of thefinished product. Such testing is, however, required to a materiallysmaller degree in the procedures of the subject invention than inconventional manufacturing operations. More important, however, is thefact that such destructive procedures, i.e., performance evaluation arecarried out on-line with the information feed back thus realizing thebenefits discussed above regarding the non-destructive procedures.

Third, the solid oral dosage units of the present invention are uniquein that they differ from conventional tablets and capsules inappearance, shape, texture, etc. and therefore have the advantage ofbeing easily identified. Also, the on-line non-destructive testingprocedures and continuous manufacturing operations of the presentinvention facilitate packaging of the unit dosage forms of the presentinvention on-line into individual containers such as, for example, clearplastic strips of blister packages thereby saving costs in handling andequipment.

Fourth, the exactness of the preparation of a solid dosage forms of thepresent invention, i.e., the uniformity of deposition of the medicamenton the web and the precision in shaping of the final units combined withthe desirable characteristics of the web itself enable the finisheddosage forms to easily meet stringent specifications, of size, shape,release of medicament and the like. The dosage forms of the inventionalso possess excellent stability and are amenable to the incorporationof medicaments which are recognized as being adversely affected bymoisture since, in certain embodiments of the present invention, themedicament is deposited or loaded to the web by electrostatic depositionthereby providing an almost total absence of moisture which might causean adverse reaction to take place. Also, wherein the dosage forms of thepresent invention are fabricated from a laminate of sheets of web,medicaments recognized in the art of pharmaceutical compounding as beingchemically incompatible can be deposited upon alternate sheets of web.This effectively stabilizes such combination without the need to resortto such economically unattractive measures as the coating of one or moreof such imcompatible substances with an insulating material, theadmixture of stabilizing adjunct materials with such medicaments, theincorporation of such medicaments into separate tablet layers which arethen pressed together and the like. Because of either or both of theseprocedures, i.e., the deposition of a medicament on the webelectrostatically as a dry powder and the placing of potentiallyincompatible medicaments alternately between sheets of a laminate, thedosage forms of the invention are advantageously useful in theadministration of effervescent formulations.

The solid oral dosage forms of the present invention are further uniquein that the medicament contained therein is completely internalizedwithin the dosage form yet, in most instances, there is no coating perse applied to the finished dosage form. This represents an additionaleconomic advantage for the dosage forms of the subject invention overconventional tablets which must be coated to obtain internalization ofthe medicament.

While the dosage forms prepared in accordance with the methods of thepresent invention are intended primarily for oral administration, dosageforms suitable for rectal and/or vaginal administration are likewisecontemplated. Modifications in the size of the web as well as thefabrication methods to be described hereinafter to produce dosage formsof the desired size and shape will be readily apparent to those skilledin the art. Certain modifications of the web composition to obtain thedesired type and pattern of release of medicament would likewise have tobe made. Tests have shown that rectal and vaginal insertion of soliddosage forms according to the invention has produced substantially nolocal irritation.

As mentioned above, the novel dosage units prepared in accordance withthe invention can be formulated or "engineered" to any desired releasepattern including sustained release. Regardless of the release pattern,the dosage units of the invention are characterized by an exceptionaluniformity of release over a large number of dosage units, e.g., tenthousand or more. The variance in release rate can be obtained inaccordance with the present invention by the manipulation of a number offactors such as, for example, the thickness of the web, the compositionof the web, the presence of an over-wrap or outside seal on thefabricated web and its composition, how tightly the web is fabricated,and the like. For example, a web composition containing a high contentof sodium carboxymethylcellulose will normally disintegrate slowly ingastric fluids. Dosage forms fabricated from such webs by fan-folding aswill be described hereinafter will open or unfold upon contact withgastric fluid thereby releasing the medicament loaded on the internalsurfaces thereof very rapidly, in fact, more rapidly than conventionaltablets and capsules presently available. However, if such a fan-folddosage form were to be sealed on the folded edges with a substance suchas, for example, ethylcellulose, cellulose acetate phthalate or zeinwhich will prevent its opening in gastric fluids, the medicament wouldbecome available by the gradual erosion of the web thereby giving asteady, sustained release of medication. Since the dosage forms preparedin accordance with the present invention are capable of releasingmedication with a rapidity superior to presently available solid dosageforms, i.e., tablets and capsules, such release represents the preferredembodiment of the present invention.

The accompanying drawings are summarized as follows:

FIG. 1 is a block diagram of the total manufacturing process indicatingpoints of on-line inspection.

FIG. 2 is a diagrammatic representation of a system capable of effectingthe process depicted in FIG. 1.

FIG. 3 is a diagrammatic representation of an arrangement for carryingout the convolute winding technique of dosage form fabrication.

FIGS. 4, 4A and FIG. 5 illustrate the rotary-forming and laminationtechniques of dosage form fabrication. FIGS. 6A-6D illustrate thefinishing and sealing aspects of the fanfolding technique of dosage formfabrication.

FIGS. 7 and 8 are graphic illustrations of the pattern of release ofactive ingredient from the dosage forms of the invention in comparisonwith a conventional solid dosage form, i.e., a capsule.

THE WEB

The webs capable of being utilized for deposition for medicament inaccordance with the present invention must meet a large, diverse numberof physical and chemical criteria to be acceptable in the practice ofthe invention. These criteria can be briefly summarized as follows:

The web must be non-toxic, edible and, particularly, not have anobjectionable "feel" in the mouth. In addition, the web preferably selfdestructs or is degradable in body fluids and/or enzymes. However, theweb can be of non-destructible substance which is readily eliminated bythe body. The web preferably is hydrophilic and readily disintegrable inwater. These properties must not be adversely affected and, preferably,be enhanced at the pH of gastric fluid;

The web must be totally inert to the medicament loaded thereto and mustnot release any substance upon dissolution with gastric fluid whichwould cause an in situ incompatibility with said medicaments;

The web must be stable over extended periods of time and at elevatedtemperatures and relative humidity and generally be a poor medium forthe growth or microorganisms;

The web must have acceptable resistivity properties so that powderedmedicament (usually possessing dielectric properties) can be loadedthereto by electrostatic deposition;

The web must possess acceptable workability and mechanical properties,i.e., it must possess sufficient elasticity to allow it to be drawn orcast into a thin sheet, i.e., from about 0.025mm to about 0.25mm inthickness, it must possess good tensile strength and tear strength andit must have acceptable fold endurance where required to withstandcertain of the fabrication methods as will be described hereinafter;

The web surface must facilitate the types of on-line analyticalprocedures described hereinafter, be capable to being coated with andretain powdered medicament electrostatically or otherwise loaded theretoand be amenable to printing operations;

The web must be readily sealable by liquid and or heat seal methods suchas are recognized in the art. The sealing, however, must be effective atlevels of moisture and heat which do not adversely affect the medicamentcontained in the dosage form. In addition, the web must possessacceptable flammability resistance so as to tolerate such sealingoperations;

In certain instances the web must possess "memory", i.e., it must havesufficient resiliency so that, upon contact with gastric fluids, it willvery rapidly reverse the fabrication process and "open" thus releasingmedication for absorption. By "opening" is meant that, for example, ifthe dosage form is fabricated by fan-folding it will open like abellows, if fabrication is by convolute winding it will uncoil, and thelike; and

The web must possess other properties such as, for example, havingacceptable taste and odor which will become apparent to those skilled inthe art from the instant disclosure.

As mentioned above, the webs utilized in the present invention arepreferably water soluble or water dispersible. There are two basicmechanisms whereby the webs of the present invention are formulated toself destruct in contact with water or gastric fluid. First, the web cancontain particles of substance such as, for example, casein, gelatin andthe like which swell upon contact with water thereby disrupting orbreaking the web. Second, the web formulation may contain both watersoluble and insoluble constituents. Upon contact with water, the solubleconstituents of such a formulation will tend to go into solution and theinsoluble constituents to precipitate thereby causing the web torupture. The latter means of disrupting the web is not as rapid as theformer. Examples of suitable water soluble constituents includemethylcellulose and the like. Examples of suitable water insolubleconstituents include ethylcellulose, and the like.

The web formulations utilized in preparing the novel dosage forms of thepresent invention are of two basic types, i.e., polymeric and paper. Thepolymeric formulations generally comprise;

(a) one or more organic film formers

(b) one or more plasticizers

(c) modifiers, i.e. other ingredients optional with certain formulationssuch as disintegrants, extenders and the like,

(d) in one or more fugitive solvents.

The paper formulations generally comprise:

(a) one or more fibrous materials

(b) one or more non-fibrous modifiers, i.e., other ingredients optionalwith certain formulations, e.g., one or more organic film formers,disintegrants, extenders and the like,

(c) in a fugitive solvent.

The film forming compound of the polymeric webs of the present inventioncomprises one or a mixture of art-recognized, non-toxic, organic filmformers such as, for example, natural and chemically modified starchesand dextrins, proteins such as gelatin; cellulose derivatives such assodium carboxymethylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose and the like; other polysaccharides such aspectin, acacia, xanthan gum, guar gum, algin and the like; syntheticssuch as polyvinylpyrrolidone, polyvinyl alcohol and the like. Preferredfilm formers are hydroxypropylcellulose and sodiumcarboxymethylcellulose. Although the concentration of the film formingcomponent in the polymeric web is not particularly critical to thepractice of the invention, it has been found that between about 5% byweight and about 95% by weight is preferred with a concentration of fromabout 40% by weight to about 90% by weight being most preferred.

The above named film forming substances are equally illustrative of thefilm forming component of the paper web formulations of the presentinvention where such is present. Preferred film formers of the paper webformulations of the invention are likewise hydroxypropylcellulose andsodium carboxymethylcellulose. The concentration of the film formingingredient in the paper web formulations of the invention is likewisenot considered critical. However, when such ingredient is present to actas a binder or disintegrant for the fibrous material, it should notexceed about 40% by weight, preferably from about 2% by weight to about20% by weight and most preferably from about 4% by weight to about 10%by weight.

The fibrous ingredient of the paper web formulations of the inventioncan be any of the commercially available natural or artifical fiberswhich have been shown by proper tests to be non-toxic. Examples of suchfibers include cotton, linen, cellulose, synthetically modifiedcellulose, rayon, textured vegetable protein, collagen and the like.

To insure the required workability and mechanical properties, thepolymer webs utilized in the practice of the invention contain aneffective amount of a plasticizing ingredient. Such ingredient mayinclude one or more members of the group of plasticizers recognized inthe art of pharmaceutical compounding such as, for example, glycerin,the polysorbates, e.g., polysorbate 80, polysorbate 60, certain mixturesof mixed mono- and di-glycerides of saturated fatty acids and the like.It is preferred that such plasticizers be present in an amountcomprising from about 1% by weight to about 60% by weight, preferablyfrom about 10% by weight to about 50% by weight of the web composition.

Both polymer and paper webs may contain one or more disintegrants suchas are recognized as being conventional in the art of disposable papersuch as, for example, various types of starches, casein, gelatin and thelike. The webs according to the invention should contain from about 0%by weight to about 40% by weight preferably from about 5% by weight toabout 20% by weight of disintegrant depending on the web formulation.

Further, both types of web formulations may contain one or more fillersor extenders which are recognized in the art as being conventional. Suchingredients include, for example, opacifier fillers such as titaniumdioxide, chalk, kaolin and the like, microcrystalline cellulose, calciumcarbonate and the like. It is to be appreciated that some of theingredients enumerated herein can function in more than one capacity andtherefore fall under more than one of the categories listed above. Forexample, calcium carbonate can function as both an opacifier anddispersant, certain starches can function as binders and asdisintegrants, etc.

In addition, both polymer and paper formulations may contain one or moremodifying ingredients which affect the electrical, mechanical, opticalor permeative properties of the webs produced therefrom. Examples ofsuch ingredients would include an electrolyte such as, for examplesodium chloride, potassium chloride and the like, surface active agentssuch as dioctyl sodium sulfosuccinate and the like. The webs may alsocontain optional ingredients such as pharmaceutically acceptablecoloring agents, preservatives, and the like.

Finally, both types of web formulations, in most instances, will containa fugitive solvent, e.g., water, certain organic solvents, for example,ethyl alcohol or combinations of such solvents i.e., a hydroalcoholicmixture which is removed during formulation of the web.

Specific examples of film compositions in accordance with the presentinvention include the following:

Polymeric films that self-destruct in an aqueous environment due to thepresence of swelling agents.

    ______________________________________                                        Ingredient              Percent by Weight                                     ______________________________________                                        I      Hydroxypropylmethyl- 45.69                                                    cellulose                                                                     Acacia               19.44                                                    Gelatin, extra fine, solubilized                                                                   32.08                                                    Dioctyl Sodium Sulfosuccinate                                                   75% aqueous solution                                                                             0.09                                                     Titanium dioxide     1.94                                                     Lecithin             0.75                                                                          100                                               II     Refined starch       33.06                                                    Carboxymethylcellulose                                                                             33.06                                                    Propylene Glycol     33.06                                                    Sodium Benzoate      0.55                                                     Sorbic Acid          0.28                                                                          100                                               III    Hydroxypropylmethylcellulose                                                                       55.19                                                    Cellulose Acetate Phthalate                                                                        2.99                                                     Corn Starch          28.66                                                    Propylene Glycol     9.87                                                     Titanium Dioxide     1.52                                                     Dioctyl Sodium Sulfosuccinate                                                                      1.52                                                     Lecithin             0.25                                                                          100                                               IV     Hydroxypropylmethyl- 64.00                                                    cellulose                                                                     Cellulose Acetate Phthalate                                                                        3.10                                                     Calcium Carbonate    21.74                                                    Propylene Glycol     9.06                                                     Titanium Dioxide     0.91                                                     Dioctyl Sodium Sulfosuccinate                                                                      0.91                                                     Lecithin             0.30                                                                          100                                               ______________________________________                                    

All of formulations I-IV are sealable by the application of heat andpressure. Formulation IV self destructs in an aqueous environment due tothe presence of insoluble polymeric agents.

Preferred paper formulations in accordance with the subject inventioncomprise from about 70% by weight to about 99% by weight, preferablyfrom about 40% by weight to about 96% by weight fiber, e.g., hardwood orsoftwood fibers or mixtures thereof, from about 1% by weight to about30% by weight, preferably from about 4 by weight to about 10% by weightof a disintegrant selected from the group consisting of sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylcellulose,polyvinylpyrrolidone and guar gum and from about 0% by weight to about5% by weight, preferably from about 0% by weight to about 2% by weightof a surfactant such as, for example, polysorbate 80, dioctyl sodiumsulfosuccinate, sodium lauryl sulfate and the like. The ability of theabove substances to function as disintegrants in paper formulations isconsidered to be unexpected in view of the fact that, where members ofthis group are utilized in paper making they are present in differentquantities and perform a different function. For example, wherein sodiumcarboxymethylcellulose has heretofore been utilized in paper making, ithas been utilized in small quantities, i.e., 0.1% by weight or less asan aid in dispersing the fibers as the paper is formed. In distinctcontrast, it has been found that when sodium carboxymethylcellulose orthe other substances enumerated above are added in large quantity, i.e.,up to 30% by weight after the paper web is formed but while it is stillwet they will function as disintegrants the time of addition of thesesubstances is critical to the function thereof as disintegrants. Thedisintegrants are added as a solution preferably in the solvent utilizedto prepare the paper web. It has been found that the above nameddisintegrants, when added to the web as herein described, coat thefibers. When the finished dosage form is contacted with water, thedisintegrant swells thus forcing the fibers to disrupt the web. Thesurfactants, where present, acts to enhance the penetration of water tothe disintegrant thus promoting disruption.

The webs utilized in accordance with the invention are formed byprocesses conventional in the arts, e.g., the paper-making and filmmaking industries. For example, the polymeric webs can be cast on anappropriate substrate, e.g., Mylar, stainless steel, release paper andthe like. The webs are then dried, e.g., in a forced-air oven. Thetemperature of the drying air and length of drying time depend on thenature of the solvent utilized as is recognized in the art. Most of thewebs contemplated herein, however, are dried at a temperature betweenabout 25° and 105°, preferably between about 60° and 90° C.

A second method of forming polymeric webs which is conventional in theart is extrusion. This method is preferred with webs wherein the filmforming ingredient is a modified food starch, hydroxypropylcellulose orother extrudable polymer. The mechanical particulars of the extrusionprocess, e.g. the particular equipment utilized, the extruding force,the shape and temperature of the orifice are considered to be within theskill of the art and can be varied in a known manner to achieve thephysical characteristics of the webs to be described hereinafter.

The paper webs of the subject invention are prepared utilizingconventional paper-making machinery such as, for example, Fourdrinierpaper making machines. In all cases, however, the web must be uniform inboth thickness and width. The webs are between about 1 and about 10 mils(about 0.003mm to about 0.03mm), preferably from about 1.5 to about 4.5mils (about 0.38mm to about 0.123mm) thick. A convenient width for suchwebs is 12 inches (30cm) although the width of the web is notparticularly critical to the practice of the invention. The web can beproduced in any length. However, in view of the fact that the noveldosage forms produced in accordance with the invention are emminentlysuited to high speed manufacture, the webs should be prepared in largequantity, e.g., 15000 feet or more which can be stored, e.g., on coresor spools.

Reference is made to FIG. 1 in which is shown in block diagram form theoverall system process for manufacturing in large numbers the variouskinds of dosage forms herein described. Block 10 of FIG. 1 representsweb production from formulations such as have been discussed above. Asthe web is produced, or shortly thereafter, it undergoes an inspectionstep (block 11 in FIG. 1) where various examinations, which may be inwhole or in part automated, are performed, to ensure the integrity ofthe web, as will be more particularly described hereinafter. It is to benoted, however, that the inspections of the web can take place as theweb is formed or at any convenient point thereafter, either by meansassociated with the apparatus making the web or by other apparatus, andmay, in fact, be performed at another location.

The active ingredient to be deposited on the web is prepared and storedfor use in container means, as is generally illustrated at 23 in FIG. 2,which figure illustrates, largely in schematic form, the variousapparatus suitable for performing the steps indicated in FIG. 1. Theprepared active ingredient is caused to be forwarded to an arrangementgenerally indicated at 23 in FIG. 2 where the active ingredient particlesize reduction and control indicated at step 12 in FIG. 1 is performed.Although this step will be discussed in greater detail hereinafter, itis intended via this step 13 and the depicted apparatus 23 to provide auniformity of flow in order to enable exact and uniform deposition(block 14 of FIG. 1) of the active ingredient on the web, which isillustrated at 24 in FIG. 2. It should be noted that the system exampledepicted in FIG. 2 pertains to the deposition of dry particulatematerial onto the web in a dry state. It is to be clearly understood,however, that the scope of this invention includes as well wetdeposition of active ingredient onto the web. FIG. 2 also illustratesschematically at 21 that embodiment of the invention wherein the web isprepared and stored for later use, i.e., the web inspection step (Step11 of FIG. 1) is performed, e.g., as the web is caused to be taken offof a storage roll 20. It is to be clearly understood that inspection maybe made prior to the web being wound and stored as well as or inaddition to being performed where and as indicated in FIG. 2 at 21. Theparticulars of web inspection are described in greater detailhereinafter.

With more particular regard to inspection means 21, inspection of theuncoated web is accomplished by several methods. Holes, blemishes, andphysical integrity of the web may be evaluated and quantified by using ascanning laser beam and photodetector combination. The system is used inboth transmission and reflection modes. The continuous helium-neon laserbeam is steered across the web by a mirror on a galvanometer. The mirrorposition is electronically controlled so that the position of any defecton the web can be located. The reflected or transmitted light isdetected by a linear photodiode located behind an interference filter toexclude room (stray) light. The electrical output is used to count thenumber of defects and determine their size and distribution along thelength of the web. This is accomplished by analyzing the detector outputsignal with a pulse height-width analyzer.

An alternate method capable of inspecting the web at significantlyhigher web speeds is a parallel array of photodiodes positioned acrossthe web. Each photodiode has its own threshold detector system anddigital logic which allows a low-resolution defect size and positionlocation characterization. The output signal can be processed to yieldapproximate size distribution and the location of the defects on theweb.

The physical thickness of the web is measured by a parallel array of webriders mounted in precision bearings. These rollers contact the web andare connected to transducers which electronically sense position to atleast 1/10,000 inch. A similar system of physical thickness can be madeof pneumatic sensors which float above the web on a fixed film of air.This system has the advantage of noncontact with the web.

Mass thickness (weight per unit area) or basis weight of the webs isdetermined by using a noncontacting beta-ray or x-ray gauge. Thesesystems measure the absorption of beta-rays or x-rays passing throughthe web. This absorption is related to mass thickness. In an alternatesystem, the electrical resistance between two contacting web-ridingelectrodes may be used to determine the basis weight of webs with knownmoisture content.

On-line analysis of moisture content can be measured by one or more ofthe following methods. First, the high dielectric content of waterallows sensitive moisture determination to be made by direct microwaveabsorption and by radio-frequency dielectric constant sensors.Low-frequency conductance measurements can also be used to measure theamount of web moisture. Infrared spectrophotometric absorption providesa totally independent moisture measuring method. Further, the opticalabsorption at wavelengths in the region of 1-2 micrometers will yield aspecific and precise moisture determination in a spectral region whereinthe web being inspected is relatively transparent.

The web, having passed the inspection means 21, is guided by a suitableroller arrangement shown in FIG. 2 to pass in close proximity to theactive ingredient deposition apparatus 24 wherein active ingredient isloaded to the web. The deposition apparatus is immediately followed bymeans 25 schematically shown for on-line analysis/inspection, e.g., forcontent uniformity of active ingredient, of the coated web preferably asa single sheet before the active ingredient has been internalized.

A preferred method for the nondestructive on-line analysis of activeingredient deposited on webs is x-ray absorption. In this method, lowenergy x-rays peaked to match the absorption edge of atoms deposited onthe web are directed through the coated web. The absorption of thex-rays is related to the active ingredient-plus-web absorption. Whereinthe active ingredient is deposited on the web by a wet-coating process,this method of analysis may be utilized either before or after thedrying step.

Since the total x-ray absorption arises from the combination of web andactive ingredient containing coating, it is necessary to determine theabsorption of the web separately. This is accomplished by means of abeta-ray gauge or an infrared spectrophotometer. Increasing sensitivityis achieved for the x-ray measurement of deposited active ingredientcontaining atoms with increasing atomic numbers. The x-rays source canbe tuned by varying the accelerating voltage to match the absorptionedge for many atoms of interest.

Reflectance or transmittance spectrophotometry may also be utilized tonondestructively analyze the deposited active ingredient on-line.Reflectance spectrophotometry is used in the near ultraviolet region todetermine active ingredient loading. This technique may be used with anysolid active ingredient having an optical absorption in a suitablewavelength region.

Transmission spectrophotometry may also be used for nondestructiveon-line analysis of active ingredient coated on webs. A suitable lightsource, monochromating element, and detector combination are selectedfor wave-length regions where the active ingredient selectively absorbs.This must be in a spectral region where the web itself does not stronglyabsorb. Such regions for webs of the present invention occur in thenear-infrared and functional group infrared regions of the spectrum. Arapid wavelength scanning system is used to sweep over a smallwavelength region of interest. The signal from the detector istime-averaged over several scans to reduce the effects of noise. Thesignal data are then processed to give a first derivative oftransmission with respect to wavelength for increased sensitivity. Thisis done in a similar fashion for other wavelength regions which aresensitive to other components in the system. Thus water content, basicweight of the web as well as active ingredient content can be determinedsimultaneously.

Another method for analysis of active ingredient loading is molecularfluorescence. Excitation radiation in the ultraviolet or visible regionof the spectrum is provided by a suitable filter combination. Thefluorescence from the active ingredient is detected by a wide-bandfilter-detector combination matching the fluorescence peak; a blockingfilter is used to remove the excitation energy. The detector for thismethod is preferably a photon counter, which counts individual photoevents, providing high sensitivity and linearity at low levels ofillumination. In this method of analysis, precautions must be taken tolimit the photodegradation of the active ingredient by the excitationradiation.

The coated web may be stored for a time or, preferably, directlyforwarded to means for fabrication (step 16 of FIG. 1) and unitizing(step 17 of FIG. 1) to form dosage forms which means are illustrated inFIG. 2 as a series of knives 26 for slicing the coated web into amultiplicity of endless strips, followed by fabricating and unitizingmeans 27 of the lamination type, i.e., the endless strips are stackedone on another to form an endless stack which is pressed and ultimatelyunitized in accordance with the invention as hereinafter described.

The unitized dosage forms are then finished and packed by appropriateapparatus (step 18 of FIG. 1) schematically illustrated at 28 and 29 inFIG. 2, for subsequent distribution. Appropriate inspection (at e.g., 30in FIG. 2) is performed in connection with this step. The purpose of thefinal inspection of individual dosage units is to verify size, shape,integrity, identity, presence and accuracy of printing, and activeingredient content. All of this inspection is done non-destructivelyexcept for active ingredient content. In order to analyze for activeingredient content and performance characteristics, a statisticallyappropriate sample of dosage units is removed from the production lineand destructively analyzed both for potency and performance, e.g.,dissolution characteristics, by solution spectrophotometry as will bediscussed hereinafter.

An optical scanning system may be used to inspect all the productionunits for size, shape, integrity, identity, and the presence andaccuracy of printing. The system comprises a suitable light source and amatrix of photodetectors or a T.V. camera. A computer is used to processthe signals from the optical system. Suitable algorithms are used todetermine the acceptability of the dosage units. Another method employsa comparison of the sample image with a standard image by means of animage-masking technique.

In another method for 100% inspection, an optical transform of the imageof the dosage unit is made. The Fourier transform spectrum, the powerspectrum, or other suitable transform is compared with a similartransform of a standard by means of a computer.

Prior to the finishing step, step 19 (FIG. 1) of on-line analysis fordissolution and content uniformity is performed by suitably arrangedapparatus not particularly illustrated, which apparatus may includeand/or by controlled by computer or similar central processing or logicmeans. A random sampling mechanism removes one dosage unit at a timefrom the end of the production line at a rate of 25 to 120 units/min.,preferably at a rate of 40-60 units/min. Each unit is sequentiallytransferred to a conventional automatic weighing device wherein it isweighed by nondestructive means and the information stored.Randomly-selected units are then sequentially placed in a conventionalautomatic analyzing system. The dosage unit is stirred in a suitablesolvent for the active ingredient at an appropriate rate. The amount ofactive ingredient dissolved at t_(j) minus the amount dissolved at t₁divided by t_(j-) t_(i) is taken as the rate of dissolution. Theappropriate time interval (t.sub. j-t_(i)) has been previously chosenand will vary with individual medicaments. A suitable time intervalmight range from 5 seconds to 2 minutes or more. The sample is thencontinuously stirred for a sufficient time to allow for all of theactive ingredient to be dissolved after which the solvent is analyzedfor content of active ingredient. The amount of active ingredient inthis analysis plus the amounts from samples t_(i) and t_(j) is the totalpresent in the dosage form. This information is also recorded andstored. If the weight, thickness, dissolution rate, and analysis of themedicament content fall within previously defined limits, the units aredeemed acceptable. If the readings do not fall within these limits, theunits produced beginning with the negative analysis and ending with thenext positive analysis are quarantined for further evaluation.

It is to be noted in FIG. 1 that further provision is made formonitoring functions to be performed in accordance with this inventionas are described hereinafter. Regarding the web insepection step, it isintended, for example, that continuous monitoring inspection of the webbe made from the standpoint of the web color, thickness, continuity,soil spots and defects of virtually any kind. These functions may beperformed by electronic and/or optical instruments as well as by visualobservation.

Inspection of the web includes the actual placing of a "flag" on the webwherever a fault or defect is detected. Additionally, apparatus may beprovided such that, whenever a defect is detected in the web a printoutis generated, either automatically or under operation control,indicating that on the web at certain distance downstream a defect ofsome sort exists, which printout would include an identification of thetype of defect, such a a hole, blackspot, blemish etc..

The means for generating the printout can be the same apparatus actuallyflagging the web per se. Such apparatus is considered conventional infabric manufacturing and fabric inspection, for example, with theexception that the handling and inspection of the web would, in theinstant case, be performed in accordance with good manufacturingpractices.

In addition, by the same or additional conventional inspection apparatusthe web thickness would be measured. This could take the form of avisual display involving an operator or could be a detecting devicecoupled to a logic arrangement having upper and lower limits for webthickness, wherein if the thickness of the web violates one of thelimits, there will also be effected a printout and a flag placed on theweb as described above. One form of apparatus for providing thicknessmeasuring of the web could take the form of an x-ray or a beta ray gaugeor some similar device for measuring the mass thickness of the web.

In the case of step 13 of FIG. 1 regarding particle size reduction andflow control, it is intended that monitoring functions be performed asdescribed in the following. In accordance with the invention,notwithstanding that the unloaded web itself has been monitored fordefects and thickness, similar monitoring is contemplated followingloading of the web with active ingredient(s). For example, x-ray gaugeapparatus would, again, be applicable to determine the loaded webthickness, which thickness, in comparison to the earlier determinedunloaded web thickness, would enable conclusions to be derived regardingthe amount of active ingredient loaded to the web. Additionally, it iswithin the scope of this invention to provide actual mass monitoringmeans in order to determine the amount of active ingredient loaded tothe web. It should be understood that performance of coated-webinspection could be effected by routing the coated web back through thesame apparatus performing the web inspection in connection with step 11in FIG. 1.

The active ingredient deposition system (reference 14 in FIG. 1) iscontrolled by feedback from the on-line analysis of active ingredientcontent on the web. For example, electrical signals from the on-lineanalyzer (digital) or analog) analyzing active ingredient loading(weight of active ingredient area of coated web) are used in a feedbackmode (reference designator 15 FIG. 1) to control the amount of activeingredient applied to the web in the deposition process. These feedbacksignals are fed, for example, to a minicomputer which produces asuitable correction signal to the deposition process. The correctionsignal causes either an increase or a decrease in the active ingredientloading so as to maintain the loading within a narrow range around thetarget value. For example, in the dry deposition process, the activeingredient powder is introduced into the deposition apparatus. Thus, thecorrection signal is used to control the feed rate and, consequently,the active ingredient loading.

In the wet deposition process, the correction signal may be utilized,for example, to vary the amount of the coating formulation which isapplied to the web. For example, the gap between metering rollers orbetween a metering knife and application roller is varied to change theactive ingredient loading. In reverse roll coating, the rotational speedof the application roller is varied to change the active ingredientloading. Another means of control in wet deposition is by variation ofthe connection of active ingredient in the coating liquid. Two liquidformulations containing different concentrations of active ingredientare mixed in the required proportions to supply the correctconcentration; the ratio of the two formulations may then be varied toaccurately control active ingredient loading.

DEPOSITION OF MEDICAMENT ON THE WEB

The methods of "incorporating" active ingredient into the novel dosageforms of the present invention constitute a radical departure frommethods of incorporation active ingredients into conventional soliddosage forms, e.g., tablets, capsules, dragees, suppositories, etc.While the methods and equipment utilized in the methods of the inventionmay vary somewhat, the overall prime object is uniformity of deposition,i.e., to deposit active ingredient on the moving web surfaces in anexceptionally uniform manner. The manner of active ingredient depositionutilized in accordance with the present invention is unique andpossesses a number of advantages over manufacturing procedures commonlyutilized in the pharmaceutical industry.

In view of the fact that the active ingredient is deposited on orsubstantially on the surface of an edible web which is then fabricatedto completely internalize it, there is no need for common pharmaceuticalexcipients, fillers, preservatives and the like to be admixed with theactive ingredient thus eliminating a cost and, more importantly, asource of potential incompatibilities and quality control problems. Theweb, in accordance with the present invention, is loaded with a uniformcoating of active ingredient and is then divided into individual dosageforms by linear or geometric subdivision thereby effecting a level ofuniformity of strength of active ingredient over a large number ofdosage units which is substantially superior to the batch requirementsnow accepted in the pharmaceutical industry. In distinct contrast,conventional pharmaceutical manufacturing operations require that theactive ingredients and suitable therapeutically inert pharmaceuticaladjunct materials are prepared in a large quantity and subdividedvolumetrically for filling into capsules or compression into tablets.Utilizing the manufacturing methods of the present invention, it istherefore possible to reduce the amount of excess active ingredientpresent to assure label dosage from the presently accepted level of from5% to 10% by weight to approximately 1% to 5% by weight therebyrealizing a substantial saving particularly when compounding veryexpensive active substances, e.g., certain hormones and antibiotics.Finally, the method of depositing or loading the active ingredient tothe web in accordance with the present invention allows for continuous,on-line, non-destructive testing of the dosage by physical parametersthereby facilitating superior uniformity of amount of active ingredientover a large number of dosage forms.

The active ingredient may be loaded to the web in either wet or dryform, with dry form being preferred. In either instance, the activeingredient is deposited in a form susceptible to analysis as will bedescribed hereinafter, i.e., a finely particulate form. The particlesize is the submicron range and can also be within a narrow size rangefrom 1 up to 100 microns. Particles in the submicron range haveheretofore been considered as being too fine for the production ofpharmaceutical tablets without first being subjected to techniques suchas granulation which substantially increases particle size and whichalso adds excipient matter to the active ingredient. The technology ofthe invention facilitates the use of such ultrafine particles withoutthe need to resort to such techniques and/or the addition of excipientmatter. The active ingredient is deposited as a very uniform coating onthe web as it is being moved in an automated manufacturing system.

The preferred method of deposition of active ingredient on the webwherein the active ingredient is a dry form is powder cloudelectrostatic deposition utilizing techniques generally recognized incertain non-pharmaceutical arts. Generally, this method requires passageof the web through an electrostatic field in a suitable chamber. Finelyparticulate active ingredient is charged as it is introduced into thechamber via, for example, a forced air stream and is deposited on theweb as it passes over an oppositely charged roller. It is readilyapparent that this is an oversimplification. However, apparatus requiredto accomplish this result is known in certain non-pharmaceutical fieldssuch as the production of adhesives and adhesive papers. For asuccessful deposition to take place, it will be apparent that the webmust have a resistivity capable of enabling the deposition thereon ofdielectric particles. Additives which can be present in the webformulation to enhance the proper electrical properties thereof havebeen discussed above. In a number of instances, it has been found that,prior to electrostatic deposition of active ingredient powder, it isnecessary to coat the web with a substance which will enhance theadherence of the powder thereto. Examples of such substances includecarboxymethylcellulose, methylcellulose and the like. These adherenceenhancing substances may be applied to the webs in a conventionalmanner, e.g., by applying a solution in a fugitive solvent such as waterand drying with, e.g., heated air. The application of a coating to theweb to insure adherence of the active substance is then immediatelyfollowed on-line by the coating or "loading" of the web with activesubstance. The adhesive is then activated to bind the particles ofactive substance to the web. This is accomplished by applying heat,pressure, moisture or a suitable combination thereof to the loaded web.In addition to the electrostatic powder cloud deposition method, fineparticulate active ingredient may be coated onto the web in a dry stateby Electrogasdynamic Power Coating. In this method, the particles ofactive ingredient are electrically charged by exposure to coronadischarge and propelled by a gas stream into an electrically insulatedchamber. The web is passed through this chamber on a metallic surfacewhich is either grounded or charged with opposite polarity to that ofthe charged cloud of particles of active substances. The electric fieldbetween these particles and the metallic surface attracts them to theweb and deposits them thereon.

Further in accordance with the present invention, active ingredient maybe coated onto the web in the form of a solution on a suspension offinely divided medicament, i.e., a collodial suspension. The liquidutilized for these operations can be water, an organic solvent, e.g.,ethanol or a hydroalcoholic solvent. A preferred method of loadingactive ingredient in a liquid form onto a moving web is electrostaticjet spray deposition. In this method, the active ingredient containingsolution or suspension is metered into an apparatus which projects aspray of microdroplets which are concentrated on a particular area ofthe web through the use of a defined area electrostatic field. Thismethod has given very good results where small quantities of activeingredients such as, for example, hormones or enzymes are to be loadedon the web. By small quantities is meant active substances having ausual dosage of less than one milligram.

In addition to electrostatic jet spray deposition, certain other coatingtechniques recognized in other arts as being amenable to the coating ofa substrate with a liquid may be utilized in loading the web with activeingredient. For example, the paper web may be passed under a roll whichis immersed in a bath of saturating fluid. As the web passes the roller,the excess fluid is "wiped" from the web by another roller, a jet ofair, a rubber wiping bar, a wire-wound rod, i.e., a Meier rod, or thelike. In this instance there is some penetration of the web by thesolution, particularly if the solvent utilized to solubilize or suspendthe active ingredient is the same or similar to that utilized to formthe paper web.

It will be appreciated that, while it is the object of the presentinvention to load the active ingredient to the surface of the web, somepenetration of the web may result either from the use of a fugitiveliquid carrier for the active ingredient or by the application of heatand/or pressure to the web to seal it. Simple experimentation with thesefactors, e.g., fugitive liquids, will determine the percentage of activesubstance loaded to the web which may be absorbed therein. Once thisparameter is established, the on-line testing apparatus as describedherein can be adjusted accordingly. Where any appreciable amount ofactive substance is absorbed into the web it is necesssary to haveunloaded web, i.e., web without active ingredient for the outer surfaceof the dosage unit thus preventing loss of active ingredient throughexposure to deteriorating forces such as air and moisture. Obviousmodifications of the fabricating processes to be described hereinafterwill accomplish this result.

As stated above, one of the obvious advantages of the dosage forms ofthe present invention is that pharmaceutically active substance can beformulated into a stable dosage form without being admixed withconventional pharmaceutical excipients which are usually present inconventional solid dosage forms in quantities far exceeding the amountof active substance. It will be appreciated, however, that small amountsof inert substances may of necessity be loaded on to the webs with theactive substance in accordance with the invention as described above.For example, wherein the active substance is loaded to the web in dryform, a small quantity, i.e., from about 0% by weight to about 10% byweight, preferably from about 1/4 % by weight to about 2% by weight ofthe active substance, of a glidant may be homogeneously admixedtherewith. The purpose of the glidant is to facilitate the flow of thepowdered active substance through the deposition apparatus. Suitableglidants include, for example, finely particulate siliceous preparationssuch as the colloidal silica marketed under the trademark Cab-O-Sil bythe Cabot Corp., Boston Mass., talc, finely particulate starchpreparations, e.g. DriFlo by National Starch, Inc. and the like. It canbe appreciated that the inclusion of a glidant and the quantity thereofwill depend on the crystalline structure and flow properties of theactive substance. In certain instances, a preservative may be admixedwith the active substance. However, wherein the active substance isloaded to the web in dry form, this is usually not required. Further, itis within the scope of the present invention to admix the adhesivesubstances referred to above with the active substance when applying inwet form and wherein both adhesive and active substance are compatiblewith the same liquid carrier. In most instances, however, the adhesivesubstances are utilized as described above wherein the active substanceis loaded to the web in dry form to enhance adherence thereto. In eitherinstance, said adhesive substance may be present in from 0% by weight toabout 100% by weight, preferably from 0% by weight to about 30% byweight based on the weight of said medicaments.

The amount of active substance loaded to the web in accordance with thepresent invention will vary according to the dosage of the saidsubstance, the area of the web to be coated, the thickness of thecoating and the like. Additional factors affecting the amount of drugloaded to the web are the method of loading utilized, the parametersdictated by the fabrication process to be described hereinafter and thetype and sensitivity of the on-line testing equipment utilized. In allinstances, however, the amount of active substance loaded to the web issuch that, when the loaded web has been fabricated and unitized, eachresultant until will contain a therapeutically efficacious dosagethereof. As an example of the latter criteria, wherein the analysis ofdrug loading uniformity is carried out utilizing spectrophotometryemploying photocounting techniques to measure the ultraviolet absorptionof the active substance of the web, the thickness of the activesubstance coating cannot exceed 0.005 centimeter. In any event, theamount of active substance loaded to the web is always expressed inmilligrams or micrograms per square centimeter of web. This isdetermined for the total web surface even though in some instances it isnecessary to leave a margin of uncoated web to be utilized for sealingthe dosage form. The capability of the webs to receive and internalizeactive substance in accordance with the subject invention is expressedas the web conversion factor (WCF) and is calculated by the followingformula. ##EQU1##

For example, if web measuring 15.25 cm× 1.0 cm is exposed to drug and isfabricated to a dosage form measuring 0.5 cm by 1.0 cm then; ##EQU2##

FABRICATION

The next step in the preparation of the novel dosage forms according tothe invention is the forming or fabrication step. As utilized herein,the term "fabrication" indicates transposing the web as initially formedinto a solid geometric form of predetermined shape divisible into aplurality of unit dosage forms. This step may take place, as in the casewith regard to the steps above-described, in a continuous manufacturingprocedure at high speed. This step transforms the loaded flat web into ashaped geometric form and, generally, substantially internalizes theactive ingredient within a protecting coating of web. The formed web isthen unitized and finished to produce pharmaceutically pleasing unitdosage forms suitable for oral ingestion. It should be noted that, in apreferred operation, unitizing would occur along with or immediatelyfollowing fabrication.

In accordance with the present invention, there are several differentmethods of fabrication, among which can be named extrusion tubing,multiple ribbon forming, over wrapped rope forming, die forming and thelike. The four principal techniques of forming or fabricating the webcoated with active substance are: convolute winding, rotary forming,fan-folding and lamination. These four principal techiques are discussedin detail below.

Before discussing the individual fabrication techniques for theinvention in detail, the various criteria for an acceptable techniqueshould be reviewed. The fabrication or forming technique should beamenable to high speed manufacturing operations and produce a geometricform to exacting specifications of uniformity. The process must becapable of substantially internalizing the active substance. Finally,the fabrication or forming process must not put excessive stress on thewebs so as to deform or tear them and must not dislodge a substantialquantity of active substance from the web. Each of the forming processesdiscussed hereinafter meet these criteria.

The first principal technique to be discussed concerns convolute windingof a moving web. It is perhaps appropriate to distinguish betweenconvolute winding and spiral winding as recognized, for example, in thepaper-converting industry. In spiral winding, the paper is fed to thespiral winding machine from several rolls where it is usually in coilsthat are 1/2 cm to 2 cm wide. The continuous strips of paper from eachroll are coiled around a cylindrical mandrel which is supported at oneend. The strips are coiled in such a way that they overlap. An adhesiveis applied to each strip of paper and the overlapping strips from acontinuous spiral as they are wound around the mandrel. The rollthus-formed is caused to rotate about the mandrel by the action of acontinuous belt which also forces the paper roll forward toward theunsupported end of the mandrel. At the end of the mandrel, the tubethus-formed is cut into desired lengths by the intermittent action of ahigh-speed knife. Paper which is converted in this way would always havea hole in the middle by virtue of the mandrel upon which it is formed.In the convolute-winding process, there is no mandrel, and, therefore,it is not necessary nor desirable to have a hole in the center of theformed rod. In fact, it is expressly intended by this invention toseverely limit or eliminate altogether this central hollow area.

Reference is made to FIG. 3 which diagrammatically illustrates oneexample of convolute winding. In the convolute winding process of FIG.3, the coated or loaded web 61 is fed from a single roll through asystem comprising, for example, guide wires 62 and roller 63 to a cutterarrangement 64 which cuts the web transversely into desired lengths,usually from about 12 cm to 25 cm in length. The sections of web arethen guided into a corrugating roller arrangement 65 wherein acorrugating roller forms a series of creases by pushing the web againsta soft rubber roller. As a result of the corrugating action, theindividual sections of web are formed or curled into loosely woundcoils. The loosely curled webs emerging from the corrugating rollerarrangement are then passed between a stationary surface and a movingsurface, wherein the space between the two surfaces is graduallydecreased along the course of travel of the curled webs. The stationaryand moving surfaces may be in the form of two concentric cylinders,wherein one is stationary and the other rotates relative to thestationary cylinder, or, as shown in FIG. 2 they may be in the form of aflat fixed plate 67 as the stationary surface and a moving belt 66 asthe non-stationary surface. As the sections of web as loosely wound rodspass between the moving and stationary surfaces, they are wound tightlyuntil a firm rod is formed. By appropriate adjustment of the spacingbetween the two surfaces, the rod can be wound tightly enough toeliminate any hole in the middle. It will, of course, be appreciatedthat, if desired, the spacing can be made so that a hole of desired sizeis left in the middle of the formed rod.

The rod can be sealed by several methods. First, it has been found thatthe conventional process of making, e.g., confectionary sticks isunacceptable in the practice of the present invention. In theconventional method the moving surfaces that come in contact with theweb during rod formation are sprayed or coated with water to contact alarge portion of the web. The amount of water absorbed by the web, about18% by weight, is unacceptable for the preparation of the unit dosageforms of the invention due to possible deleterious effect on theadhesion of the medicament to the web as well as on the medicamentitself. Further, the rods formed by this conventional process have beenfound for the most part to be too tightly sealed to give a good releaseof medicament in the body. It has been discovered in accordance with thepresent invention that spraying approximately the same portions of theweb as in the conventional process with a sufficient amount of a finespray of water to merely damper it and rapidly drying the rods afterformation yields final dosage forms possessing acceptable uniformity andrate of release of medicament as well as stability in terms of theactive ingredient with the obvious exception of those medicaments whichare recognized in the art of pharmaceutical compounding as being highlysensitive to the presence of moisture.

Second, the rods may be sealed by the application of a piece ofheat-sealable edible polymer to the trailing edge of each sheet of webor the trailing edge of each sheet is coated with a heat-sealable,edible polymer directly after the cut is made from the endless web.Alternately, a heat-sealable polymer may be applied over the entiresection of web either as a separate sheet or as a uniform coating.Suitable polymeric material would include, for example, a water-solublepolyoxyethylene or cellulose ether derivative containing a plasticizersuch as is described above. After the rods are tightly wound, they arein such an instance made to pass under a heated plate where both heatand pressure are applied to effect a seal. For example, a portion offixed plate 67 could contain a heated section.

Alternately, the rods, after formation, may be sealed by the applicationof water or an adhesive to the outer layer(s) or web. Preferably, wateris used as the sealing agent. This method would likely require thepresence of substances in or on the web composition, for example,starches or starch derivatives, which would form a seal throughsubsequent drying or with the application of heat and pressure.

The method illustrated in FIG. 3, for purposes of example, provides fora water spray 68 to contact the outer surface of the endless belt 66along to lower, return portion thereof, such that the belt surfacecontacted by the rolled web sections retains only enough water, dropletsto effect a proper seal of the rods. The water could also be applied tothe tightly wound rods, for example by passing them under a watertransfer roller, a porous plate through which a metered quantity ofwater is uniformly applied to the total length of the rods, or a spongearranged to apply water to the outer surfaces of the rods. The rodscould then be caused to pass between a further section of the moving andstationary surfaces where pressure or pressure and heat may be appliedto effect the completed seal.

This general method of effecting a water seal is deemed clearly superiorto known methods of forming, for example, confectionery sticks asdescribed above. With the water application methods as above-describedthe total amount of water applied to each rod is less than that appliedby known methods. As a result, the amount of water to be removed duringsubsequent drying of the rods is substantially less than that generallyrequired with known methods.

The rods thus-formed are each as long as the width of the web of thesupply roll. This width is typically 20 to 40 cm. After each rod issealed, it is caused to move into contact with, for example, ultrasharpknives 69 (FIG. 3) via the belt 66 where it is utilized, i.e., the rodis cut to desired lengths. Methods for unitizing and finishing theserods to final dosage forms are discussed below in further detail.

A second forming or fabrication method to be considered is generallyidentified as rotary forming. This method can take several specificforms. This method may be considered as being related to the moregeneric lamination method in that, in this method, stacks of web loadedwith active substance in endless strip or rod arrangements are initiallyprepared either by fan-folding of lamination, both of which arediscussed hereinafter. In one specific rotary forming method, asillustrated in FIG. 4, a continuous, relatively thick strap of stackedwebs of web 70 loaded with active substance is passed between a pair ofpress rollers 71. The continuous thusly formed or pressed laminatedstack 72 is fed to a second station, i.e., a rod shaping and densifyingstation, comprising, for example, one or more spring loaded stainlesssteel rollers 73 having a circumferential edge shaped to transform thestrap into a plurality of continuous rods 74, or largely circular orother desired cross-section. The rods 74 shaped thereby into desiredgeometric form are then passed through a third rotary station where, forexample, one or more pairs of suitably arranged rollers unitizes therods into individual doses. This may be followed by other suitableprinting and finishing operations as are more particularly describedhereinafter. It should be noted that the printing operation could becarried out in the unitizing step involving the third set of rollers 75.

Another example of rotary forming is shown in FIG. 5 wherein the formedendless stack (strip or rod) 81 is continuously indented at regularintervals by reciprocating die blocks 82 and/or a pair of suitableheated rollers 83 to provide ultimately rounded corners in the finaldosage units, such that the output of the rotary dosage forming stationis a continuous chain of end-connected dosage units 85. As with all orthe various methods of rotary forming according to the invention, thethusly altered rods are passed through printing and unitizing stationsor subassemblies, all at high-speed.

In another closely related rotary forming technique, the continuousstack is fed into a rotary shaping and densifying assembly comprised asbefore of, for example, one or more pairs of stainless steel rollers.The layers of web, which may be made from layers of paper and polymerfilm, are heated and compressed into a continuous stack. It ispreferable that the outer layers of the stack be paper, for example, toprevent sticking of the stack assembly to the heated rolls. During thisdensifying operation, the layers of web are bounded together as a unitwhich reduces shifting of the layers and splitting of the edges duringsubsequent side- and end-forming operations. Next, the ends of thedosage units are formed by feeding the continuous rectangular stackproduced at the densifying station into a second station where the endsof the dosage units are formed by a pair of heated rollers which mayhave shaped, transversely-oriented cutters located on the rollers faces.The cut ends of the dosage are shaped and sealed by the heat from therolls. The configuration of the end cutter determines the shape of theends of the dosage units. The shape of the end cuts is designed toprovide a smooth transition with the side cuts of the dosage units whichare performed in the next station.

The sides of the dosage units are formed in the laminated end-formed,cut material stack with a third pair of heated rolls. These rolls mayhave angular grooves with raised cutting edges. The configuration of thegrooves in the roll faces forms a desired dosage unit cross-section.Heat and pressure applied from the ridge-like cutting elements on therolls seals the sides of the dosage units into a smooth surface.

The rotary-forming method of dosage unit fabrication illustrated in FIG.5 consists, therefore, of three primary stations, viz. apre-densification station, an end-forming station, and a side-formingstation. Each of these stations consists of a set of rollers, preferablyheated, through which the continuous web stack is passed. Theconfiguration of the outside surface, i.e., the face of the rollers ateach of the stations is different, depending on the particular stationand the result to be accomplished. Various additional operations, suchas additional cutting, printing, or finishing steps can be performedbetween or at the three stations described. These operations aredescribed further below.

It is to be noted that it is within the scope of the invention toprovide one or more of the various steps in the rotary forming methodsimultaneously, and, in fact, perform on the endless laminate inputstrap, via a single pair of, for example, spring-loaded, heatedcooperating rollers, all of the various above-discussed steps, i.e.,rod-forming, dosage-forming, unitizing and even printing.

The above-described third example of rotary forming readily lends itselfto an example of combining two or more of the outlined steps into one.Such is illustrated in FIG. 4A wherein essentially the laminating pressand rod-forming steps of the above-discussed third rotary forming methodand also the method as illustrated in FIG. 4 are combined, for example,through the use of a single pair of heated, pressing and cutting rollers(not particularly shown) which simultaneously press the laminate feedand end cut it into a shape resembling a side view of a plurality ofstacked doughnuts. These end cut sections are then immediately fed to aunitizer which provides the longitudinal cuts enabling the individualdosages to be realized. The printing step, for example, could also beperformed at this latter station. It is also within the concept of thepresent invention to package the unitized dosage forms directly as theycome from the unitizing operation, for example, by inserting them intoblister strips by apparatus considered conventional in the art.

A third method of forming dosage forms in accordance with the presentinvention is the fan-folding technique. One could also classify thefan-folding technique as being a form of lamination in a general sense.In this method, a web up to, for example, 30 cm wide is first fabricatedto internalize the active ingredient loaded thereon. This may beaccomplished either by initially folding the web in half or bylaminating two coated webs with the coated surfaces facing. A stack ofmore than one pair of webs laminated in this manner may be utilized, thewebs may initially be formed, for example, to a greater width, i.e., upto 60 cm and, following lamination, divided to form two or more widthsof a size described for the fan-folding operation, i.e., from about 1 cmto about 15 cm.

After the coated web has been initially folded or laminated as describedabove, it is then passed through scoring rolls where it is scored inpreparation for the fan-folding operation. The scoring rolls may or maynot be powered. The web is basically moved by pulling rods. Scoring canbe accomplished, for example, by spring-loading one of the pair ofscoring rolls. Since the web folds preferentially in the direction ofthe score rings which impress into the web material, the score rings maybe positioned alternately in the upper and lower rolls in accordancewith the desired fan-fold pattern. The scored web then passes into afan-folding chute having folding blades which begin to gently bend theweb at point of contact and constrict both in width and overlap so thatthe web is reasonably tightly folded at the discharge end. At the end ofthe fold chute is a means for pulling the web through the scoring andfolding apparatus such as, for example, a pair of stainless steel,spring-loaded driven rollers. This serves a dual function, i.e., the webis moved through the folding apparatus and the folded web is compactedinto a continuous, solid geometric form. It is, of course, within thescope of this invention to combine the pulling means with means forsealing the web. However, the fan-folded web may be sealed by othermethods as will be described hereinafter. The sealed webs may beunitized in a number of ways such as the rotary forming method describedabove.

In FIGS. 6A-6D one fan-folded dosage form technique is illustratedwherein the initial fan-folded webs 91 are assembled in perforations 92Aof cooperating shape in a therapeutically inert web structure,preferably comprised of paper, identified as center strap 92. This"loaded" center strap bearing the fan-folded webs is then sandwichedbetween outer straps of web 93 to form a composite laminated structure.This composite endless laminated strap is then fed to, for example, arotary dosage forming unit or station not unlike that of unit 83 of FIG.5, wherein the strap is caused to take on the appearance of that shownin FIG. 6B. Finally, or simultaneously with the step performed inrelation to FIG. 6B, the unitizing step is performed, renderingindividual dosages such as illustrated in FIG. 6C. FIG. 6D illustratesin cross section the dosage form illustrated in FIG. 6C. FIG. 6D showshow the fan-folded webs 91 are completely internalized and that, e.g.,the center strap 92 is forced by the molding process outwardly somewhatso that some of it is exposed between the edges of outer straps 93 whichare sealed thereto. It should be noted that, preferably, outer straps 93and center strap 92 are free of any active ingredient thereby ensuringthat none of the active ingredient will be present on any exteriorsurface of the individual dosage forms.

The fourth principal forming method contemplated by this invention isthe lamination method generally alluded to hereinbefore. In this method,between about 20 to 60 rolls of web are first simultaneously unwoundfrom a multiple-reel unwind stand and then guided together to form acontinuous rod. The 20 and 60 layers of web may all be paper-likematerial with an appropriate coating to facilitate sealing in asubsequent step, or they may be a laminate of a paper-like web and aheat-sealable, edible polymer web, or they may consist of one or morepaper-like webs alternately interspersed with heat-sealable, ediblepolymer webs. Suitable polymeric materials include, for example, awater-soluble polyoxyethylene or cellulose ether derivative containing aplasticizer. Any number of the webs may be loaded with active substance.Preferably the paper composition webs are loaded with active substance.

An alternate method for stacking the webs which are loaded with activeingredient is to supply them directly from the deposition apparatus. Thewidth of the web is usually 12 to 25 cm. The web, as stored on rolls orsupplied from the deposition apparatus, may initially be multiple of thefinal width which is slit to the final desired width as part of thestacking process.

Once the web is stacked, the continuous resultant bundle is guided to alamination station. Apparatus known in diverse arts for bringing stripsof flexible films together and forming a laminate therefrom is generallyapplicable to the practice of this embodiment of the present invention.As already discussed, the area of deposition of active substance on theweb strips of sheets will vary depending, for example, on the method ofsealing the lamination. The cutting and finishing of the laminate maylikewise vary in accordance with the invention. For example, laminatescan be treated as in the rotary forming process described above.However, the lamination station could also consist of a pair ofreciprocating die plates which form, seal, and cut dosage forms from thecontinuously feeding web stack. A typical die plate would have a surfaceof approximately 25 cm× 25 cm.

The laminates formed in accordance with the present invention are, in aparticular embodiment, unique in that they are sealed only at the edgesas opposed to each sheet being totally sealed to the adjacent sheets. Ithas been found that, unexpectedly, suitable dosage forms can be producedfrom a stack of layers of web wherein up to six layers of papercomposition web are interspersed between layers of a web comprises of aheat sealable polymeric composition by the application of heat andpressure to the stack by the cutting means during unitizing. During theunitizing operation, the layers of polymeric web in the stack becomedeformed by the heat and pressure and "spread" to cover and seal theedges of the intervening layers of paper composition. It is readilyapparent that the top and bottom layers of such a laminate must be ofpolymeric composition. It is preferred that the medicament in apaper-polymeric web stack be loaded to the paper layers of web. It isreadily apparent from the foregoing disclosure that such a laminatesealed only at the periphery possesses a superior rate of release ofmedicament than a similar stack of webs which has been totallylaminated.

An alternative method for forming the dosages from the web stack is topass the stack between rotating cylinders which have individual dualdies on the outer periphery. The dosage units are formed, sealed and cutfrom the continuously feeding web stack as it passes between suchrotating cylinders.

Some pharmaceutical compounding benefits are realized from the use oflaminating techniques are herein considered. First, the laminatingtechniques provide barriers which facilitate the compounding of two ormore therapeutically active substances which are incompatible withoutthe need to resort to the addition of stabilizing substances or aspecial compounding technique such as, for example, encapsulation of oneor more ingredients. Since up to, for example, 60 layers may be utilizedto form a laminate, this embodiment of the invention is ideally suitedfor pharmaceutical preparations containing a large number of activesubstances where there are numerous possibilites of incompatibilitiessuch as, for example, multivitamin preparations. Further, the insulatingeffect of layers of a laminate and the deposition or loading of activesubstance to the web in the dry state makes such techniques ideallysuitable for the dispensing of effervescent preparations. In suchpreparations, it is appreciated that the web composition would have tobe such that it would readily dissolve or disperse in water. Also, asdiscussed above, loading of the active ingredient onto the web in thedry state is advantageous wherein the active substance is adverselyaffected by moisture.

Further regarding the laminate process of the present invention, it iswithin the scope thereof to vary the formulation of the various layerswithin a laminate as well as to control whether each is coated withactive substance. Obviously, the surface of the top and bottom layers ofa laminate which will be exposed is not coated thus providing effectiveinternalizing of the active substance. For, example, it has been foundthat interspersing one or more layers of a starch-based formulation in acellulosic laminate more expediently adds plasticity to the laminatethan increasing the quantity of plasticizer in the formulation of thecellulose layers.

Regarding the method of forming discussed above, it is preferred inaccordance with the invention to deposit of load the web with activeingredient in the wet form wherein forming is by the convolute wind orfanfold process. The rotary forming and lamination processes are equallyamenable to deposition of active substance in wet or dry form with thechoice being dependent on the characteristics of active ingredient beingloaded, for example, solubility in the particular solvent beingutilized, stability to moisture, and the like.

UNITIZING

As a practical matter, unitizing cannot be discussed without alsodiscussing sealing, and without first having discussed fabrication,since, by definition, cutting or unitizing the formed webs could exposesome active ingredient at one or more of the outer surfaces. Anexception to this would be having the loading operation adapted todeposit active substance at short intervals as opposed to a continuousdeposition thereby having active substance "spot deposited" andsurrounded on all sides by uncoated web. In view of considerations ofmanufacturing equipment and the need to maintain integrity of thedeposition coating for on-line testing, it is preferred to load activesubstance continuously onto the web in sufficient amount so that theunitizing operation produces dosage forms containing a therapeuticallyefficacious dosage. In certain of the operations described herein, e.g.,the fan-folding process, the outer margins of the web may be left freeof active substance to insure internalizing of the active substance and,in certain instances provide excess web which can be utilized to sealthe unitized dosage forms.

The cutting of the formed web must be accomplished in such a manner soas not to deform the web. The cutting operation itself may beaccomplished by stationary or rotary knife blades, by single- ortwo-stage dies, or by other conventional methods. To assure that thefabricated web will not be deformed during the cutting operation,several cuts may be made from different angles. Also, as discussed abovewith regard to rotary forming, the formed web can initially be crimpedslightly or indented to compensate for the distortion caused by the highspeed unitizing operation.

The formed, loaded web may be unitized by individual separation, i.e.,the formation of one unit at a time such as by cutting exact lengthsfrom a rod or, preferably, a number of units may be formedsimultaneously such as by cutting a convolute wound rod into a number ofdosage units utilizing a number of uniformly spaced cutting edges.Another method of forming a plurality of dosage units simultaneouslywould be the use of shaped dies, either single or double and rotarymounted, or reciprocally mounted on plates to cut a laminated web or aconvolute wound rod-like structure. The shape of the final dosage formpreferably has cosmetic appeal and is such that a number of shapes willfit into a die plate with essentially no waste except at the periphery arectangle, a square or, preferably, a hexagon.

The shape of the dosage forms prepared from rods can also be determinedby the shape of the cutters. The cutter, for example, could be ofrectangular shape with the parallel larger sides moderately concaved sothat the ends of the dosage forms cut therewith will be slightlyrounded. Other variations will be apparent to those skilled in the art.It is to be borne in mind, however, that such lateral support as isrequired to prevent wrinkling and flashing must be applied to thefabricated dosage forms during the unitizing operation.

It is within the scope of the present invention to combine the unitizingand final sealing operations. Although there are numerous ways by whichthe dosage forms can be sealed, the most commonly combined with theunitizing operation are heat and/or pressure. In addition to effecting aseal on the severed edges of the dosage form by heating the cuttingtool, heat and pressure can be applied through the die to bond thelaminate. Also, the use of moisture or a fugitive solvent to seal thetrailing edge of the convolute wound rod as mentioned above can beextended to the cutting operation by applying such solvent to thecutting surface. Heat and/or pressure may also be applied at the sametime to ensure a proper seal.

The methods whereby the unitizing dosage forms prepared in accordancewith the present invention may be sealed are not unconventional to theplastics handling and laminating arts. These include, in addition to theuse of water or other fugitive solvents such as, for example, ethanol,methanol and chloroform, the application of pressure and heat, theapplication to a separate adhesive, infrared heating, ultrasonicbonding, encapsulating or combinations of two or more of these. Apreferred method of sealing dosage forms within the scope of the presentinvention in the use of an overwrap which may be preprinted if desired.This may be, for example, a thin layer of edible polymeric material suchas, hydroxymethyl cellulose, modified starch, and gelatin which issprayed on the dosage units of a bath into which the dosage units areimmersed. Such layer could be self sealing such as, for example, byremoval of a fugitive solvent. More preferred methods of effecting asealing layer on the unitized dosage units in accordance with theinvention are encapsulation and basket sealing.

In the first of these methods, the solid dosage units are passed betweenconverging layers of flexible film of, for example, gelatin whichenclose the dosage form such as that illustrated in FIG. 6A. The gelatinfilm is then heat sealed and cut to shape. Apparatus for encapsulationof liquids by this method is recognized in the pharmaceutical industryand such apparatus can readily be adapted to coat the novel dosage formsof the present invention.

A second method is basket sealing which may be accomplished by at leastthe following two processes. In the first, preformed baskets areprepared from material such as, for example, gelatin, or a cellulosederivative by apparatus well known, e.g., in the art of plastic molding,i.e., injection molding. The unitized dosage forms are placedautomatically into these backets at high speed and the baskets are thencovered by an overlayer which is sealed to the basket by any of thesealing methods alluded to herein, preferably utlrasonic welding. Thebaskets are separated by cutting with a stationary or rotary cuttingedge. The walls or the preformed basket are usually thicker than the topor sealing layer. The sealing layer, however, is sufficiently thick toprotect the dosage form yet is such that the dosage form will bereleased from the basket via the sealing layer within a very short timeafter ingestion, usually within a few seconds after reaching thestomach. Alternately, the basket may be formed from identical halveswhich are sealed by methods such as have been described herein.

An alternative to the basket seal described above is to form acontinuous support web or strap of material such as described above forthe basket and cut holes therein to exactly accomodate the dosage form,e.g., fan-folded dosage forms as illustrated in FIG. 6A. In thisembodiment, the unitized dosage forms are placed into the holes, e.g.,by a pin through the hole and a second pin on top of the unitized dosageform to keep it under compression. The strap is then sealed by theaddition of a top and bottom layer of similar material while maintainingcompression on the dosage units. The thickness of the strap is in noinstance more than that of the dosage units. The strap, however, can bethinner than the dosage form but not less then approximately half thethickness thereof. It is preferred that the support strap be close to orequal to the thickness of the dosage form for a number of reasons.First, the sealing film can be as thin as that described above inconnection with the basket since it is not significantly distorted inthe sealing operation. Second, a thicker support web will be lesssubject to distortion during the perforating and unitizing operations.Third, holes can be made closer together in a thicker strap thusallowing for a minimum of waste. Once the dosage form has been placed inthe support and sealed, the strap is again unitized as described herein.An advantage to both the basket and support strap concept describedabove is that there is web material on the outer surface which does notcontain active substance and which could be subjected to finishingoperations such as, for example, embossing, beveling, and the likewithout risk of loss of active substance. Also, the use of the basket orthe support strap concepts facilitate the use of varying colors in thefinal dosage form, e.g., by making the support web, sealing strips orthe dosage units themselves contrasting colors, an especially pleasingand distinctive appearance may be achieved.

The material to be utilized in preparing the basket, center supportstrap and sealing films describe above must, as is the case with thewebs themselves, meet critical tests. In addition to the obviouspharmaceutical criteria of purity, having good shelf life, beingnon-toxic and compatible with the active substance utilized, thematerial must have good surface quality, color and ink respectively,structural integrity, deformability, dimensional stability and releaseof active ingredient in water. The preferred substances for this use arehydroxypropylcellulose and methylcellulose. An especially preferredcomposition comprises hydroxypropylcellulose, a starch or starchderivative as an extender and disintegrant, a plasticizer such as, forexample, polyethylene glycol, suitable pigments, e.g., titanium dioxideand an antioxidant such as, for example, BHT.

QUALITY ASSURANCE

One of the major advantages realized by the novel dosage forms of thesubject invention is that they are amenable to on-line, non-destructivequality assurance. In the context of the present invention the term"non-destructive" is meant in the practical sense as opposed to thestrict literal definition. By this is meant that quality assurance ofthe novel dosage forms of the invention is provided during high-speedmanufacturing procedures with the actual loss of substantially less than1% of the dosage form. Since the novel dosage forms of the invention canbe produced with a low standard deviation in dosage and therefore amanufacturing excess of less than the standards conventionally acceptedin the pharmaceutical industry at the present time, the very smallpercent of the dosage form lost during testing becomes in essence, zerowhen viewing the tolerances of the instant manufacturing process intotal.

The novel dosage forms of the present invention, as a finished product,possess quality assurance of the manufacturing process, a concept uniquein the pharmaceutical industry. The on-line testing procedures givingsuch assurance are to be clearly distinguished from such recognizedpharmaceutical quality control procedures as chemical and physicalcontrol of the ingredients of the dosage form before the manufacturinghas begun, destructive testing of solid dosage forms after themanufacturing procedure has been completed both for physicalcharacteristics, e.g., dissolution rates, incidence of capping and thelike and chemical characteristics such as potency, presence ofincompatibilities and the like and physical quality checks of soliddosage forms such as, for example, manual inspection of bicoloredcapsules to assure that each has ends with contrasting colors. Suchtests, which are recognized and commonly practiced in the pharmaceuticalindustry and described in the official compendia, bear no relation toand are not suggestive of the on-line manufacturing assurance which is acritical feature of the solid dosage forms of the invention. It is to benoted, however, that certain conventional procedures such as, forexample, strict quality and testing of all ingredients prior to themanufacturing process form an integral part of the preparation of thedosage forms contemplated herein as is the case with any goodpharmaceutical manufacturing practice.

The on-line quality assurance of manufacturing possessed by the noveldosage forms of the present invention is provided by the fact that allsuch forms described herein begin with a continuous edible web which canbe tailored to non-destructive testing. First, the web production itselfis monitored for the physical characteristics of the web to assure thatthe web is uniform and is free of defects. For example, the web can bemade to pass through a resonant cavity where a microwave passing throughthe web is continuously monitored for web thickness, i.e., once theresonant frequency is established, changes therein are indicative ofchanges in web thickness. Other means of monitoring web thicknessinclude laser beam diffraction, fluidic sensing and physical contactsensors. It is also possible in accordance with the present invention totest the web for weight per unit area and for defects.

The preferred method of testing the web for weight per unit area is softx-ray absorption, e.g., a wavelength of about 4 angstroms. Beta-rayabsorption unitizing a PM 147 source is also feasible. Web defects suchas specks, holes and streaks can be detected by laser beam scanning.Holes in the web can be detected by the electrical discharge methodutilizing equipment which is commercially available.

The methods detailed above are equally applicable in those instanceswhere the web receives a second coating either in the form of one or anumber of additional webs or a protective coating applied to a loadedweb. Laser scanning is particularly advantageous to the on-line qualityassurance of such coatings.

A second major area of quality on-line assurance in accordance with themethod of the present invention is monitoring of the amount of activesubstance deposited onto the web and also the uniformity of the coatingoperation. It must initially be remembered that a distinct advantage ofthe process by which the novel dosage forms of the present invention areproduced is that the active substance is loaded to the web in a formwhich is amenable to the testing procedures to be described hereinafter,i.e., in finely particulate form or as a fine film.

There are several methods contemplated herein for analysis of uniformityof deposition of active substance. For example, a photon counter can beutilized to measure ultraviolet absorption of the highly attenuatingactive substance-web system. Soft x-ray absorption utilizing awavelength of about four Angstroms and beta-ray absorption can also beutilized. Light scattering apparatus is preferred since it is ideallysuited for monitoring particle size and concentration in the powdercloud or on the web. The apparatus suitable for such operations iscommercially available.

The fabrication, unitizing and finishing steps described above arelikewise amenable to on-line procedures such as described above inconnection with the web. Such tests will, of course, involve physicalparameters of the web after fabrication such as dimension, thickness,uniformity and the like. Similar tests are also carried out on theunitized dosage forms regarding shape, uniformity and the like.

The discussion to this point has centered on means whereby the noveldosage units of the invention are tested non-destructively on-lineduring production. Two additional tests are contemplated within thescope of the invention and without departing from the spirit of theterminology "non-destructive testing".

In the first such operation, a minute portion of the web is periodicallyremoved on-line by cutting with knives, dies, fluid jets or a laserbeam. It is comtemplated that the portion of web removed will notdestroy the integrity of the web or adversely affect any of thefabrication operations. The sample of the web can be removed before orafter the active substance is loaded thereon or, in some instances,during early stages of fabrication, e.g., when a few webs have beenstacked in a preliminary laminating or folding operation. The samplethus removed is chemically analyzed both for web composition and foractive substance. This analysis is also carried out on a quantitativebasis particularly with reference to active substance.

In addition to the spot analysis, the finished dosage forms are sampledand subjected to performance assurance on-line. While such testing is aprocedure required at present with most solid dosage forms marketed inthe United States it is not carried out on-line during the manufacturingoperation as is the case with the present invention. First, it must beborne in mind that the novel dosage forms of the present invention arenot encumbered by batch restrictions by virtue of the process wherebythey are manufactured. A "batch" in accordance with the invention cantherefore be the number of dosage units falling between two sampleswhich meet the performance specifications provided that said number doesnot exceed the sampling requirements of the Federal Food and DrugAdministration. Since the sampling procedures contemplated in accordancewith the invention substantially exceed such requirements, a "batch" ofnovel dosage units claimed herein can be any convenient number, e.g. thenumber of units which can be produced from a given production lot ofactive substance.

A second unique aspect of the performance assurance testing of the noveldosage forms of the subject invention is that the results of such tests,as well of those of all other on-line tests discussed herein, can becomputerized and utilized to adjust the parameters of the manufacturingprocess. By so doing, a negative reading on any of the tests signifiesthe beginning of a run of dosage units which must be isolated and thenext following positive result after corrections are made automaticallyterminates the run. The dosage units produced between these two testsmust then be further tested to determine how many conform tospecifications. Where tests are being conducted on-line on the web, e.g.on the amount of active substance desposited, a negative reading can beautomated to simultaneously actuate two functions. First, the web can bemarked with a spot of non-toxic dye thus allowing for the productionprocedure to be temporarily halted and a section of web manuallyremoved. Second, the reading, through a computer, actuates an adjustmentin the amount of active substance being loaded onto the web to eitherincrease or decrease said amount to conform to specifications. When theweb passing the testing unit again conforms to specifications, a secondspot will automatically be made on the web thus marking the length ofweb not meeting specifications. Similar operations are established ateach of the on-line test sites.

Regarding the performance analysis operation, random samples of finisheddosage units are removed and automatically deposited in aliquots of testsolution and tested for dissolution rate. The particular criteriautilized to test for dissolution of the unit dosage forms will vary withthe active substance or substances present therein. For example, asample dosage unit can be added to a suitable solvent thereby forming asolution of the active ingredient. The resulting test solution can bephotometrically scanned to record the concentration of active ingredientas a function of time after the test unit was inserted therein. Otherpossible indicators which could be measured in the test solution arechanged in pH, color, heat, chemical reaction and the like. Meanswhereby each of these changes can be automatically recorded as afunction of time are within the skill of the art. Once the dissolutioninformation is recorded, it can be utilized by a system such as acomputer to make such adjustments in the formation, unitizing, finishingand sealing operations as are required to correct or improve thereadings.

The on-line testing procedures described herein are in all instancesamenable to testing of the entire web, e.g., a device which tests forweb thickness. However, in certain instances testing of the entire webmay not be feasible from the standpoint of economics. For example, it ispossible to test a small area of web using a light scattering sensor andfurther possible to mount two or more sensing devices in close proximityto scan a corresponding number of small widths within a passing web. Thecost of equipment required to have the total web scanned may, however,be prohibitive. Therefore, where only limited areas of the web can bechecked, the testing equipment can be mounted on means which facilitateits oscillating across the width of the web. The percentage of web andtherefore finished dosage units tested in this manner far exceeds anynon-destructive testing procedures presently carried out in thepharmaceutical industry.

FINISHING AND PRINTING

As discussed at various points herein, the finishing operations for thenovel dosage forms of the present invention may be conductedindependently or, preferably, in combination with other operations,e.g., unitizing. Finishing in terms of the novel dosage forms of thepresent invention is divisible into two basic considerations, i.e. theuniformity of the surface of the dosage form and the finish orappearance of the surface thereof.

Uniformity of surface of the dosage forms of the invention may or maynot be a problem depending on the technique employed to unitize thedosage forms from the continuous stack and whether a sealing operationis performed. For example, wherein a laminated stack of webs is cut to aparticular shape as described above, a small flashing may be evidentwhere the cutting means meet. Also, there may be some end or sideflashing from the unitizing operation in dosage forms formed by otherpreferred methods of fabrication. Generally, however, the fabricationtechniques of the present invention minimize the incidence of suchflashing.

Flashing as described herein is generally removable by mild abrasionsuch as, for example, by subjecting the dosage units to mild tumblingaction with or without the presence of a mild abrasive substance such assalt crystals. It is realized that such action must, in most instances,precede printing operations.

The surface appearance, i.e., the gloss of the dosage forms of thepresent invention may vary from a mildly buffed appearance to reasonablyhigh gloss depending on the technique utilized and the finish desired.Wherein sealing techniques such as, for example, the basket sealing orencapsulation methods referred to above are utilized, the gloss of thefinished surface can be adjusted as desired by merely the selection ofmaterial utilized in forming the seal. The same is true wherein anoverwrap is utilized to seal the dosage forms. Wherein such sealingoperations are employed, complete removal of the flashing is usually notrequired since the overwrap assures complete continuity of surface.

The printing operation is likewise dependent on the fabrication andsealing techniques utilized. Printing may be effected on the web itselfat any convenient point in the overall manufacturing operation. Forexample, the outer layer of a laminated dosage form may be printed priorto the fabrication operation, as part of the unitizing operation, oreven after unitizing is completed. Dosage forms prepared by, e.g.,convolute winding, can be printed while still in the continuous rod orstack. Wherein the dosage forms of the invention are sealed by theapplication of an overwrap, printing is preferably carried out after theoverwrap is applied although it is within the scope of the invention toprint on the dosage form and apply a clear overwrap thereafter. Theprinting of solid unit dosage forms prior to completion of compoundingthereof as is comtemplated herein is a concept unique in thepharmaceutical industry.

The selection of a printing method is dependent on a variety of factorsthe most important of which is the physical nature of the substrate tobe printed. The selection of an appropriate method is likewise relative,to a degree, to the point in the overall manufacturing operation whereprinting is carried out, i.e., whether the web would be printed prior tofabrication, the finished dosage forms would be printed or printingwould be carried out at some intermediate point, perhaps in combinationwith other operations such as, for example, unitizing. The printingmethod and apparatus inherent thereto can be selected from thefollowing: offset and direct letterpress; offset gravure; lithograph;electrostatic powder gravure; electrostatic screen stencil; ink jet andthe like. Of these, offset gravure is the method of choice althoughother methods may be utilized in particular instances and new methods ofprinting as come to hand and are adaptable to the technology describedherein are considered to be within the scope of the invention.

It will be readily apparent from the foregoing discussion of finishingand printing operations that there are a number of ways in which thecolor of the novel dosage forms of the present invention can be variedboth in hue and intensity. First, the web composition itself can containa color which can build in intensity as layers of web are joined duringthe various fabrication operations. The color may also be imparted by anoverwrap or sealing layer. Wherein the basket or encapsulation methodsof sealing are utilized, two or more contrasting colors may be possibleby the obvious expedient of varying the color of the various sectionsthereof. The dosage forms prepared by lamination are also amenable tovariations in color simply by varying the color of the webs fed into thelaminating apparatus. Other variations of these techniques will bereadily apparent to those skilled in the art.

ACTIVE INGREDIENT

The novel dosage forms of the present invention are, as a practicalmatter, unrestricted in terms of the type of active substance for whichthey can serve as a vehicle. The terms "active substance", "activeingredient" and "medicament" which are considered to be synonymous inthe context of the subject invention and are utilized interchangeablythroughout the instant specification and claims can be defined as anysubstance which will produce a pharmacologic response in the body. Suchsubstances include but are by no means intended to be restricted to thefollowing:

The benzodiazepines such as, for example, chlordiazepoxide, diazepam,flurazepam, oxazepam, chlorozepate and the like. Additional compoundsfalling under the heading "benzodiazepines" are described in "TheBenzodiazepines" Garattini, Mussini and Randal, Raven Press 1973 thedisclosure of which is not intended as a limitation on the term;

Other tranquilizing agents such as, for example, reserpine,thiopropazate and phenothiazine compounds such as perphenazine,chlorpromazine and the like;

Sedatives and hypnotics such as the phenobarbitals, methylprylonglutethimide, ethchlorvynol, methaqualone and the like;

Psychic energizers such as, for example, amitriptyline, imipramine,methylphenidate and the like;

Narcotic and non-narcotic analgesics such as codeine, levorphanol,morphine, propoxyphene, pentazocine and the like;

Analgesic - antipyretics such as, for example, aspirin, phenacetin,salicylamide and the like;

Anti-inflammatories such as, for example, hydrocortisone, dexamethazone,prednisolone, indomethacin, phenylbutazone and the like;

Antispasmodics/anticholinergics such as, for example, atropine,papaverine, propantheline, dicyclomine, clindinium and the like;

Antihistamine/antiallergenics such as, for example, diphenhydramine,chlorpheniramine, tripelennamine, brompheniramine and the like;

Decongestants such as, for example, phenylephrine, pseudoephedrine andthe like;

Diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide,triamterene, spironolactone and the like;

Nutritional substances such as, for example, vitamins, essential aminoacids and the like;

Anti-Parkinsonism agents such as, for example, L-DOPA alone and incombination with potentiators such as N¹ -DL-Seryl-N²-(2,3,4-trihydroxybenzyl) hydrazine;

Androgenic steroids such as, for example, methyltestosterone andfluoxymesterone;

Progestational agents such as, for example, progesterone, ethisterone,norethynodrel, norethindrone, medroxyprogesterone and the like;

Estrogens such as, for example, estrone, ethinyl estradiol, diethylstilbestrol and the like;

Hormonal preparations such as, for example, the prostaglandins, ACTH andthe like;

Antibiotic/anti-infectives such as, for example, the penicillins,cephalophorins, tetracycline, chlortetracycline, streptomycin,erythromycin, sulfonamides such as sulfisoxazole, sulfadimethoxine,sulfamethoxazole and other agents such as nitrofurazone, metronidazoleand the like;

Cardiovascular agents such as, for example, nitroglycerin,pentaerythritol tetranitrate, isosorbid dinitrate, digitalispreparations, e.g. digoxin and the like;

Antacids/antiflatulents such, for example, aluminum hydroxide, magnesiumcarbonate, simethicone and the like;

Other therapeutic agents and/or combinations of agents such as arerecognized in the medical arts as being therapeutically useful.

The active substances as utlized in the subject invention may be in thefree form or in any non-toxic pharmaceutically acceptable form whereintheir therapeutic activity is retained. For example, acidic substancesmay be present as esters or as salts with pharmaceutically acceptableinorganic bases such as for example, the sodium salt, the potassium saltand the like or organic bases such as amines or quaternary forms. Basicsubstances may be present as salts with organic acids such as theacetate, the tartrate and the like. Certain substances such as, forexample, ampicillin may be present in a hydrated form. In general, anypharmaceutically equivalent form of a given active substance which isrecognized in the pharmaceutical compounding arts for said substance isutilizable in the dosage forms of the present invention subject, ofcourse, to the limitation of imcompatibility with the web substrate. Inthose few instances where such incompatibilities may exist, they arereadily ascertained by simple experimentation.

The amount of the active substance or combination of substances to beincorporated into the novel dosage forms of the subject invention isusually the amount recognized as being an effective therapeutic dosagefor the particular medicament. In general, the amount of activeingredient present in a single dosage form should not exceed about 500mg with a practical upper limit being about 750 mg.

DISSOLUTION

As stated herein, the novel dosage forms of the present inventionpossess an extremely consistent rate of release which is alsocontrollable to meet desired specifications. Therefore, whatever patternof release is contemplated, the dosage forms of the subject inventionexhibit a consistency of rate of release within such pattern which issuperior to that exhibited by conventional solid dosage forms, e.g.,tablets and capsules.

FIG. 7 graphically illustrates the superiority in release rate of thedosage forms of the invention in comparison with a conventional solidoral dosage form, i.e., commercial capsules. In the experimentillustrated in FIG. 7, six randomly sampled conventional capsules eachcontaining a like amount of the same active ingredient were each placedin 100 ml. of Artificial Gastric Fluid, U.S.P. (without enzyme). Thefluid was maintained with stirring at 37° C. The fluid in each of thereaction flasks was constantly filtered and circulated through flowcells in an appropriate spectrophotometer.

The absorbance of the fluids was read at one minute intervals and thepercent of active ingredient dissolved calculated for each reading. InFIG. 7 the fastest and slowest dissolving sample of each group are shownand the shaded area between covers the remaining four samples. ViewingFIG. 7, two conclusions are readily reached. First, the novel dosageforms of the subject invention dissolve much more rapidly than theconventional capusles tested. Second, the variation among six samples ofthe dosage units of the invention was strikingly less than of theconventional capsules tested. These results clearly demonstrate thesuperior consistency of release which is characteristic of the dosageforms of the present invention.

The blood level curves depicted in FIG. 8 also compare the novel dosageforms of the subject invention with commercially available capsulescontaining the same amount of the same active ingredient. The bloodlevel curves are theoretically drawn based on two rates of input into aone-compartment pharmacokinetic model. The blood level curves are basedon a theoretical 100% absorption of the amount of active ingredientreleased from the dosage form at a point in time and so are proportionalto the dissolution rate. The difference in blood level curves istherefore a function of dissolution rates. It is clearly evident fromthe data illustrated FIG. 8 that the dosage forms of the subjectinvention not only reach effective blood levels more rapidly but attaina higher blood level of active ingredient than the conventionalcapsules. The ability to attain a higher blood level of activeingredient more rapidly is a distinct advantage particularly in theadministration of certain types of chemotherapeutic agents, e.g.,antiobiotics, cardiac active agents and the like.

We claim:
 1. A method of preparing solid pharmaceutical unit dosageforms comprising loading one or more medicaments to a therapeuticallyinert, edible web, fabricating said web into a solid geometric form ofpredetermined dimensions having said medicament substantiallyinternalized, said form being divisible into a plurality of unit dosageforms, said fabrication comprising forming a stack of said webs arrangedso that substantially no medicament is loaded to an outer surfacethereof, cutting said stack to unitize same into unit dosage forms andsimultaneously sealing only the edges of said unit dosage forms byapplying heat and pressure during said cutting procedure therebycompletely internalizing said medicament, said procedure including atleast one non-destructive testing operation to assure uniform quality ofsaid unit dosage forms.